BACKGROUND: Eritoran tetrasodium (E5564), a structural analogue of the lipid A portion of endotoxin (lipopolysaccharide or LPS), is an antagonist of LPS and other Toll-like receptor 4 (TLR4) ligands. Eritoran tetrasodium quantitatively blocks LPS response in vivo in animal and human endotoxemia models and demonstrates a long pharmacokinetic half-life, but a short pharmacodynamic half-life. The objective of this study was to assess the safety, and pharmacokinetic and pharmacodynamic profile of E5564 infused twice-daily at three target steady-state plasma levels of approximately 1, 3 and 10 microg/ml in healthy volunteers. RESULTS: Loading and maintenance doses of up to 77 mg over 3 days in females and 105 mg over 6 days in males were safe and well-tolerated except for self-limiting phlebitis at the drug infusion site. Plasma levels reached steady state by 24 h. The C(max), C(min), and C(88), AUC(0 -infinity) were dose proportional and gender independent. Pharmacodynamic activity measured by an ex vivo LPS challenge assay, demonstrated dose-dependence for both E5564 and LPS and plasma levels of approximately 3 microg/ml E5564 or greater blocked up to 1 ng/ml LPS. CONCLUSIONS: Every 12-h dosing of E5564 can replace continuous infusion, while maintaining uninterrupted blocking of high-dose LPS.
BACKGROUND:Eritoran tetrasodium (E5564), a structural analogue of the lipid A portion of endotoxin (lipopolysaccharide or LPS), is an antagonist of LPS and other Toll-like receptor 4 (TLR4) ligands. Eritoran tetrasodium quantitatively blocks LPS response in vivo in animal and humanendotoxemia models and demonstrates a long pharmacokinetic half-life, but a short pharmacodynamic half-life. The objective of this study was to assess the safety, and pharmacokinetic and pharmacodynamic profile of E5564 infused twice-daily at three target steady-state plasma levels of approximately 1, 3 and 10 microg/ml in healthy volunteers. RESULTS: Loading and maintenance doses of up to 77 mg over 3 days in females and 105 mg over 6 days in males were safe and well-tolerated except for self-limiting phlebitis at the drug infusion site. Plasma levels reached steady state by 24 h. The C(max), C(min), and C(88), AUC(0 -infinity) were dose proportional and gender independent. Pharmacodynamic activity measured by an ex vivo LPS challenge assay, demonstrated dose-dependence for both E5564 and LPS and plasma levels of approximately 3 microg/ml E5564 or greater blocked up to 1 ng/ml LPS. CONCLUSIONS: Every 12-h dosing of E5564 can replace continuous infusion, while maintaining uninterrupted blocking of high-dose LPS.
Authors: Nikolay N Kuzmich; Konstantin V Sivak; Vladimir N Chubarev; Yuri B Porozov; Tatiana N Savateeva-Lyubimova; Francesco Peri Journal: Vaccines (Basel) Date: 2017-10-04